Inhibitors of farnesyl-protein transferase
The present invention is directed to piperazine-2,3-dione compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
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Claims
1. A compound which inhibits farnesyl-protein transferase of the formula A: ##STR27## wherein: R.sup.1a and R.sup.1b are independently selected from:
- a) hydrogen,
- b) aryl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, CN(R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- vc) unsubstituted or substituted C.sub.1 -C.sub.6 alkyl wherein the substitutent on the substituted C.sub.3 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N-- C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.10 C(O)--NR.sup.10 --;
- R.sup.2 and R.sup.3 are independently selected from: H; unsubstituted or substituted C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8 alkenyl, unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or substituted aryl, ##STR28## wherein the substituted group is substituted with one or more of: ##STR29## and R.sup.2 and R.sup.3 are optionally attached to the same carbon atom; R.sup.4, R.sup.6 and R.sup.7 are independently selected from: H; C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, aryl, aroyl and arylsulfonyl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) aryl,
- c) halogen,
- d) HO, ##STR30## f) --SO.sub.2 R.sup.11, or g) N(R.sup.10).sub.2; or
- R.sup.5 is selected from: C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) aryl,
- c) halogen,
- d) HO, ##STR31## f) --SO.sub.2 R.sup.11 or g) N(R.sup.10).sub.2;
- R.sup.8 is independently selected from:
- a) hydrogen,
- b) aryl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cyanophenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NH--, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NH--;
- R.sup.9 is selected from:
- a) hydrogen,
- b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.10 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
- R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl and aryl;
- R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
- A.sup.1 and A.sup.2 are independently selected from: a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, O, --N(R.sup.10)--, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m;
- V is selected from:
- a) hydrogen,
- b) aryl,
- c) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and
- d) C.sub.2 -C.sub.20 alkenyl,
- W is imidazolyl;
- X is bond, --CH.sub.2 --, --C(.dbd.O)--, or --S(.dbd.O).sub.m --;
- Z is selected from:
- 1) a unsubstituted or substituted group selected from aryl, arylmethyl and arylsulfonyl, wherein the substituted group is substituted with one or more of the following:
- a) C.sub.1-4 alkyl, unsubstituted or substituted with:
- C.sub.1-4 alkoxy, NR.sup.4 R.sup.6, C.sub.3-6 cycloalkyl, aryl, HO, --S(O).sub.m R.sup.5, or --C(O)NR.sup.4 R.sup.6,
- b) aryl,
- c) halogen,
- d) OR.sup.4,
- e) NR.sup.4 R.sup.6,
- f) CN,
- g) NO.sub.2,
- h) CF.sub.3;
- i) --S(O).sub.m R.sup.5,
- j) --C(O)NR.sup.4 R.sup.6, or
- k) C.sub.3 -C.sub.6 cycloalkyl; and
- 2) unsubstituted C.sub.1-C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, unsubstituted C.sub.3 -C.sub.6 cycloalkyl or substituted C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted C.sub.1 -C.sub.6 alkyl and substituted C.sub.3 -C.sub.6 cycloalkyl is substituted with one or two of the following:
- a) C.sub.1-4 alkoxy,
- b) NR.sup.4 R.sup.6,
- c) C.sub.3-6 cycloalkyl,
- d) --NR.sup.4 C(O)R.sup.6,
- e) HO,
- f) --S(O).sub.m R.sup.5,
- g) halogen, or
- h) perfluoroalkyl;
- m is 0, 1 or 2;
- n is 0, 1, 2, 3 or 4;
- p is 0, 1, 2, 3 or 4;
- q is 1 or 2;
- r is 0 to 5, provided that r is 0 when V is hydrogen;
- t is 1; and
- u is 4 or 5;
2. The compound according to claim 1 of the formula A: ##STR32## wherein: R.sup.1a is independently selected from: hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.1b is independently selected from:
- a) hydrogen,
- b) aryl, cycloalkyl, R.sup.10 O--, --N(R.sup.10).sub.2 or C.sub.2 -C.sub.6 alkenyl, and
- c) unsubstituted or substituted C.sub.1 -C.sub.6 alkyl wherein the substitutent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, cycloalkyl, alkenyl, R.sup.10 O-- and -N(R.sup.10).sub.2;
- R.sup.3 is selected from H and CH.sub.3;
- R.sup.2 is selected from H; ##STR33## and C.sub.1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
- 1) aryl,
- 2) OR.sup.4,
- 3) SR.sup.5, SO.sub.2 R.sup.5, or ##STR34## and R.sup.2 and R.sup.3 are optionally attached to the same carbon atom; R.sup.4 and R.sup.6 are independently selected from:
- H; C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) halogen, or
- c) aryl;
- R.sup.5 is selected from:
- C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) halogen, or
- c) aryl;
- R.sup.8 is independently selected from:
- a) hydrogen,
- b) C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.10 O--, R.sup.10 C(O)NR.sup.10 --, CN, NO.sub.2, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, --N(R.sup.10)2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) C.sub.1 -C.sub.6 alkyl substituted by C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.10 O--, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
- R.sup.9 is selected from:
- a) hydrogen,
- b) C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, CN, NO.sub.2, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, --N(R.sup.10).sup.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.10 O--, R.sup.11 S(O).sup.m --, R.sup.10 C(O)NR.sup.10 --, CN, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
- R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl and aryl;
- R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
- A.sup.1 and A.sup.2 are independently selected from: a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.10 --, O, --N(R.sup.10)-- and S(O).sub.m;
- V is selected from:
- a) hydrogen,
- b) aryl,
- c) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and
- d) C.sub.2 -C.sub.20 alkenyl, and
- W is imidazolyl;
- X is --CH.sub.2 -- or --C(.dbd.O)--;
- Z is selected from:
- 1) a unsubstituted or substituted group selected from aryl, arylmethyl and arylsulfonyl, wherein the substituted group is substituted with one or more of the following:
- a) C.sub.1-4 alkyl, unsubstituted or substituted with:
- C.sub.1-4 alkoxy, NR.sup.4 R.sup.6, C.sub.3-6 cycloalkyl, aryl, HO, --S(O).sub.m R.sup.5, or --C(O)NR.sup.4 R.sup.6,
- b) aryl,
- c) halogen,
- d) OR.sup.4,
- e) NR.sup.4 R.sup.6,
- f) CN,
- g) NO.sub.2,
- h) CF.sub.3;
- i) --S(O).sub.m R.sup.5,
- j) --C(O)NR.sup.4 R.sup.6, or
- k) C.sub.3 -C.sub.6 cycloalkyl; and
- 2) unsubstituted C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, unsubstituted C.sub.3 -C.sub.6 cycloalkyl or substituted C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted C.sub.1-C.sub.6 alkyl and substituted C.sub.3 -C.sub.6 cycloalkyl is substituted with one or two of the following:
- a) C.sub.1-4 alkoxy,
- b) NR.sup.4 R.sup.6,
- c) C.sub.3-6 cycloalkyl,
- d) --NR.sup.4 C(O)R.sup.6,
- e) HO,
- f) --S(O).sub.m R.sup.5,
- g) halogen, or
- h) perfluoroalkyl;
- m is 0, 1 or 2;
- n is 0, 1, 2, 3 or 4;
- p is 0, 1, 2, 3 or 4;
- r is 0 to 5, provided that r is 0 when V is hydrogen;
- t is 1; and
- u is 4or 5;
3. The compound according to claim 1 of the formula B: ##STR35## wherein: R.sup.1a is selected from: hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.1b is independently selected from:
- a) hydrogen,
- b) aryl, cycloalkyl, R.sup.10 O--, --N(R.sup.10).sub.2 or C.sub.2 -C.sub.6 alkenyl, and
- c) C.sup.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cycloalkyl, alkenyl, R.sup.10 O--, or --N(R.sup.10).sub.2;
- R.sup.3 is selected from H and CH.sub.3;
- R.sup.2 is selected from H; ##STR36## and C.sub.1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
- 1) aryl,
- 2) OR.sup.4,
- 3) SR.sup.5, SO.sub.2 R.sup.5, or ##STR37## and R.sup.2 and R.sup.3 are optionally attached to the same carbon atom; R.sup.4 and R.sup.6 are independently selected from:
- H; C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) halogen, or
- c) aryl;
- R.sup.5 is selected from:
- C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) halogen, or
- c) aryl;
- R.sup.8 is independently selected from:
- a) hydrogen,
- b) C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.10 O--, R.sup.10 C(O)NR.sup.10 --, CN, NO.sub.2, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) C.sub.1 -C.sub.6 alkyl substituted by C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.10 O--, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 N--C(NR.sup.10), R.sup.10 C(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
- R.sup.9 a is hydrogen or methyl;
- R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl and aryl;
- R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
- A.sup.1 and A.sup.2 are independently selected from: a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.10 --, O, --N(R.sup.10)--, or S(O).sub.m;
- V is selected from:
- a) hydrogen,
- b) aryl,
- c) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and
- d) C.sub.2 -C.sub.20 alkenyl, and
- X is --CH.sub.2 -- or --C(.dbd.O)--;
- Z is selected from:
- 1) a unsubstituted or substituted group selected from aryl, arylmethyl and arylsulfonyl, wherein the substituted group is substituted with one or more of the following:
- a) C.sub.1-4 alkyl, unsubstituted or substituted with:
- C.sub.1-4 alkoxy, NR.sup.4 R.sup.6, C.sub.3-6 cycloalkyl, aryl, HO, --S(O).sub.m R.sup.5, or --C(O)NR.sup.4 R.sup.6,
- b) aryl,
- c) halogen,
- d) OR.sup.4,
- e) NR.sup.4 R.sup.6,
- f) CN,
- g) NO.sub.2,
- h) CF.sub.3;
- i) --S(O).sub.m R.sup.5,
- j) --C(O)NR.sup.4 R.sup.6, or
- k) C.sub.3 -C.sub.6 cycloalkyl; and
- 2) unsubstituted C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, unsubstituted C.sub.3 -C.sub.6 cycloalkyl or substituted C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted C.sub.1 -C.sub.6 alkyl and substituted C.sub.3 -C.sub.6 cycloalkyl is substituted with one or two of the following:
- a) C.sub.1-4 alkoxy,
- b) NR.sup.4 R.sup.6,
- c) C.sub.3-6 cycloalkyl,
- d) --NR.sup.4 C(O)R.sup.6,
- e) HO,
- f) --S(O).sub.m R.sup.5,
- g) halogen, or
- h) perfluoroalkyl;
- m is 0, 1 or 2;
- n is 0, 1, 2, 3 or 4;
- p is 0, 1, 2, 3 or 4; and
- r is 0 to 5, provided that r is 0 when V is hydrogen;
4. The compound according to claim 3 of the formula C: ##STR38## wherein: R.sup.1b is independently selected from:
- a) hydrogen,
- b) aryl, cycloalkyl, R.sup.10 O--, --N(R.sup.10).sub.2 or C.sub.2 -C.sub.6 alkenyl, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cycloalkyl, alkenyl, R.sup.10 O--, or --N(R.sup.10).sub.2;
- R.sup.3 is selected from H and CH.sub.3;
- R.sup.2 is selected from H; ##STR39## and C.sub.1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
- 1) aryl,
- 2) OR.sup.4,
- 3) SR.sup.5, SO.sub.2 R.sup.5, or
- 4) ##STR40## and R.sup.2 and R.sup.3 are optionally attached to the same carbon atom; R.sup.4 and R.sup.6 are independently selected from:
- H; C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) halogen, or
- c) aryl;
- R.sup.5 is selected from:
- C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) halogen, or
- c) aryl;
- R.sup.8 is independently selected from:
- a) hydrogen,
- b) C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.10 O--, R.sup.10 C(O)NR.sup.10 --, CN, NO.sub.2, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- c) C.sub.1 -C.sub.6 alkyl substituted by C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.10 --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.1 OC(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
- R.sup.10 is independently selected from hydrogen, C.sup.1 -C.sub.6 alkyl, benzyl and aryl;
- R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
- X is --CH.sub.2 -- or --C(.dbd.O)--;
- Z is selected from:
- 1) a unsubstituted or substituted group selected from aryl, arylmethyl and arylsulfonyl, wherein the substituted group is substituted with one or more of the following:
- a) C.sub.1-4 alkyl, unsubstituted or substituted with:
- C.sub.1-4 alkoxy, NR.sup.4 R.sup.6, C.sub.3-6 cycloalkyl, aryl, HO, --S(O).sub.m R.sup.5, or --C(O)NR.sup.4 R.sup.6,
- b) aryl,
- c) halogen,
- d) OR.sup.4,
- e) NR.sup.4 R.sup.6,
- f) CN,
- g) NO.sub.2,
- h) CF.sub.3;
- i) --S(O).sub.m R.sup.5,
- j) --C(O)NR.sup.4 R.sup.6, or
- k) C.sub.3 -C.sub.6 cycloalkyl; and
- 2) unsubstituted C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, unsubstituted C.sub.3 -C.sub.6 cycloalkyl or substituted C.sub.3 -C.sub.6 cycloalkyl, wherein the substituted C.sub.1 -C.sub.6 alkyl and substituted C.sub.3 -C.sub.6 cycloalkyl is substituted with one or two of the following:
- a) C.sub.1-4 alkoxy,
- b) NR.sup.4 R.sup.6,
- c) C.sub.3-6 cycloalkyl,
- d) --NR.sup.4 C(O)R.sup.6,
- e) HO,
- f) --S(O).sub.m R.sup.5,
- g) halogen, or
- h) perfluoroalkyl;
- m is 0, 1 or 2; and
- p is 0, 1, 2, 3 or 4;
5. The compound according to claim 4 of the formula D: ##STR41## wherein: R.sup.1b is independently selected from:
- a) hydrogen,
- b) aryl, cycloalkyl, R.sup.10 O--, --N(R.sup.10).sub.2 or C.sub.2 -C.sub.6 alkenyl, and
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cycloalkyl, alkenyl, R.sup.10 O--, or --N(R.sup.10).sub.2;
- R.sup.2 and R.sup.3 are independently selected from: hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.4 and R.sup.6 are independently selected from:
- H; C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl and aryl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) halogen, or
- c) aryl;
- R.sup.5 is selected from:
- C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl, unsubstituted or substituted with:
- a) C.sub.1- 4 alkoxy,
- b) halogen, or
- c) aryl;
- R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl and aryl;
- R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
- X is --CH.sub.2 -- or --C(.dbd.O)--;
- Z is mono- or bicyclic aryl, mono- or bicyclic arylmethyl or mono- or bicyclic arylsulfonyl, unsubstituted or substituted with one or two of the following:
- 1) C.sub.1-4 alkyl, unsubstituted or substituted with:
- a) C.sub.1-4 alkoxy,
- b) NR.sup.4 R.sup.6,
- c) C.sub.3-6 cycloalkyl,
- d) aryl,
- e) HO,
- f) --S(O).sub.m R.sup.5, or
- g) --C(O)NR.sup.4 R.sup.6,
- 2) aryl,
- 3) halogen,
- 4) OR.sup.4,
- 5) NR.sup.4 R.sup.6,
- 6) CN,
- 7) NO.sub.2,
- 8) CF.sub.3;
- 9) --S(O).sub.m R.sup.5,
- 10) --C(O)NR.sup.4 R.sup.6, or
- 11) C.sub.3 -C.sub.6 cycloalkyl;
- m is 0, 1 or 2; and
- p is 0, 1, 2, 3 or 4;
9. The compound according to claim 5 which is:
- 1-(4-imidazolyl)-4-(2,3-dimethylphenyl)piperazine-2,3-dione ##STR44## or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1.
11. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 2.
12. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 3.
13. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 6.
14. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.
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WO 96/37204 | November 1996 | WOX |
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Type: Grant
Filed: Mar 25, 1997
Date of Patent: Jan 12, 1999
Assignee: Merck & Co., Inc. (Rahway, NJ)
Inventors: Christopher J. Dinsmore (Schwenksville, PA), Theresa M. Williams (Harleysville, PA)
Primary Examiner: Emily Bernhardt
Attorneys: David A. Muthard, Mark R. Daniel
Application Number: 8/823,923
International Classification: A61K 31495; C07D40306; C07D40106;